Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55](Cl)(=[O:57])=[O:56])=[C:50]([CH:59]([CH3:61])[CH3:60])[CH:49]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:57])=[C:50]([CH:59]([CH3:60])[CH3:61])[CH:49]=2)(=[O:40])=[O:41])=[CH:35][CH:34]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE 1.0 g, 2.71 mmol) and 2 mL of Et3N in 20 mL of CH2Cl2 was added 4-chlorosulfonyl-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester the (Intermediate 65, 1.6 g, 3.25 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.76 g, 79%) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O-:3])=[O:2].FC(F)(F)S(O[C:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:6]=2)[CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl (2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (16 g, 43.9 mmol, 1.0 equiv.) in 1,4-dioxane (320 mL) were added cyclopent-1-en-1-yl trifluoromethanesulfonate (11.4 g, 52.7 mmol, 1.2 equiv.), Pd (PPh3)4 (2.54 g, 2.2 mmol, 0.05 equiv.) and a solution of Na2CO3 (5.6 g, 52.7 mmol, 1.2 equiv.) in water (160 mL) at room temperature. The reaction was then heated to 110° C. and stirred for 4 h. The reaction mixture was filtered through celite then concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 32% yield).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:20]3[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCC1CCC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (47% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.74, 7.73, 7.57, 7.35, 6.98, 4.03, 3.89-3.66, 3.40-3.31, 2.36, 2.09-2.00, 1.92-1.57. 13C NMR (75 MHz, CDCl3) δ 167.6, 134.3, 132.4, 129.5, 127.2, 127.0, 126.9, 126.8, 126.7, 125.5, 121.8, 112.6, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 462.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[OH2:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=4)=[CH:13][CH:14]=3)[C:9]([C:29](=[O:33])[C:30]([OH:35])=[O:31])=[CH:8]2)=[CH:27][CH:28]=1
Reactant: O
Reactant: Fc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(O)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared from 1-(4-fluorobenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indole and oxalyl chloride in substantially the same manner, as described in Step 3 of Example 25. The product was obtained as a white solid; mp: 158-159° C. Mass spectrum (ESI, [M+H]+) m/z 458. 1HNMR (400 MHz, DMSO-d6): δ 14.00 (br s, 1H), 8.74 (s, 1H), 8.43 (s, 1H), 7.77 (d, 2H, J=6.7 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.59 (dd, 1H, J=8.7 Hz and 1.7 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.18 (t, 2H, J=9.1 Hz), and 5.61 ppm (s, 2H). Elemental Analysis for C24H15F4NO4.0.2 H2O: Calculated: C, 62.53; H, 3.37; N, 3.04. Found: C, 62.31, H, 3.20; N, 3.12.
Reaction SMILES: [BH3-]C#N.[Na+].[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH:20]=O)[CH3:9])[CH3:6].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O)(=O)C>CC#N>[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH2:20][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH3:9])[CH3:6]
Reactant: CN1CCNCC1
Reactant: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(C)Oc1ccc2c(c1CN1CCN(C)CC1)OCO2
Reaction time: 3 h
Yield: 74 %

Procedure:
NaCNBH3 (6.4 g, 101.8 mmol) was added to a stirred solution of 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (16.0 g, 67.2 mmol) and 1-methylpiperazine (20.2 g, 201.7 mmol) in CH3CN (150 ml). Acetic acid (10 ml) was added dropwise to the solution in one hour at room temperature, to keep the pH neutral (pH=7). After 3 hours of additional stirring, most of the CH3CN was evaporated in vacuo. Aqueous NaOH (2N, 300 ml) was added and the resulting mixture was extracted with diethyl ether (3 times). The combined ether extracts were washed with an aqueous solution of Na2CO3, dried over Na2SO4, filtered and evaporated to yield 26 g of a crude oil. This oil was purified by flash chromatography (eluent gradient; dichloromethane/methanol/25% aqueous ammonia=95/4.5/0.5 to 85/14/1 (v/v) to give 5-(1-ethoxyethoxy)-4-(4-methyl-piperazinylmethyl)-1,3-benzodioxole (16.0 g, 74% yield, compound No. 4) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH2:11])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2].[N-:15]=[C:16]=[O:17].[K+]>O.C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH:11][C:16]([NH2:15])=[O:17])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: NCCNc1ccc([N+](=O)[O-])cc1Cl
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 2 h
Yield: 92.4 %

Procedure:
100 g (0.46 mole) of 4-nitro-2-chloro-N-(β-aminoethyl) aniline is dissolved in a liter of water to which 29 cm3 of acetic acid has been added. 41.3 g (0.51 mole) of potassium isocyanate is added to this reaction mixture, which is then left at the ambient temperature for 2 hours. Drying yields 110 g of 4-nitro-2-chloro-N-(β-ureidoethyl) aniline which, after washing with dilute acetic acid and with water, followed by recrystallization in nitromethane, melts at 188° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:33](=[O:34])[CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)Cc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.43 mmol) and triethylamine (88 μL, 0.64 mmol) in methylene chloride (20 mL) was added dropwise phenylacetyl chloride (70 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 10 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 95 mg (61%) of the title compound as white crystals: mp 151-152° C.; [α]21D -4.3° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[C:41]([Cl:53])[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:41]([Cl:53])[CH:40]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-chloro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COC(CBr)OC
Reactant: CC(=O)c1ccc(O)c(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Temperature: 65 °C
Yield: 56.6 %

Procedure:
1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 83.8 mmol), Cs2CO3 (54.6 g, 167 mmol) and 2-bromo-1,1-dimethoxy-ethane (14.78 mL, 126 mmol) was dissolved in DMF (125 mL) under an atmosphere of nitrogen. The reaction was heated to 65° C. for 6 hours. The reaction was determined to be complete by LC/MS. The reaction was taken up in EtOAc (500 mL) and washed with 5% LiCl(aq) (3×250 mL). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (12.99 g, 57%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [O:1]1[C:12]2[C:4](=[CH:5][C:6]3[S:10][CH:9]=[N:8][C:7]=3[CH:11]=2)[O:3][CH2:2]1.Br[C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[N:18][CH:19]=1.COC1N=CC(C2SC3C=CC=CC=3N=2)=CN=1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:1]1[C:12]2[C:4](=[CH:5][C:6]3[S:10][C:9]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[N:18][CH:19]=4)=[N:8][C:7]=3[CH:11]=2)[O:3][CH2:2]1
Reactant: c1nc2cc3c(cc2s1)OCO3
Reactant: CNc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: COc1ncc(-c2nc3ccccc3s2)cn1
Product: CNc1ccc(-c2nc3cc4c(cc3s2)OCO4)cn1
Temperature: 170 °C
Yield: 35.7 %

Procedure:
To [1,3]Dioxolo[4,5-f][1,3]benzothiazole (98 mg, 0.55 mmol) and 5-bromo-N-methylpyridin-2-amine (112 mg, 0.60 mmol) were subjected to the procedure used for the preparation of 2-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole, with the following is exceptions: 5 mol % bis(tri-t-butylphosphine) palladium (0) was used and the reaction was heated under argon at 170° C. in a microwave oven for 30 min. The crude material was purified by flash chromatography (Heptane/EtOAc 1:1) to give the title compound (56 mg) as a yellow solid. 1H NMR. δ 8.62 (d, 1 H) 7.94 (dd, 1 H) 7.61 (s, 1 H) 7.47 (s, 1 H) 7.19 (q, 1 H) 6.57 (d, 1 H) 6.13 (s, 2 H) 2.85 (d, 3 H); MS m/z (M+H) 286.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:30](=[O:32])[CH3:31])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of acetic anhydride are added to 0.06 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzoisothiazol-3(2H)one 1,1-dioxide, and the mixture is stirred at room temperature for 12 hours. It is then evaporated to dryness, isopropyl ether is added and the mixture is stirred for 1 hour. It is then filtered and the colourless crystals are dried in vacuo.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 9.6 %

Procedure:
After N-methylaniline(1.5 ml, 14 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.9 g, 6.6 mmol) and dimethylformamide(10 ml), 0.25 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:14][C:15](O)=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH2:18][NH:19][C:20]([NH2:22])=[S:21].C(=O)([O-])[O-].[Na+].[Na+]>>[N:8]1([CH2:14][C:15]2[S:21][C:20]([NH2:22])=[N:19][N:18]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NNC(N)=S
Reactant: O=C(O)CN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CN2CCOCC2)s1
Yield: 27.3 %

Procedure:
(4-Morpholinyl)acetic acid trifluoroacetic acid salt (1.0 g) and thiosemicarbazide (0.25g) are heated in polyphosphoric acid (2.0 g) at 70° C. for 1 h. The mixture is cooled to room temperature and basified with sodium carbonate, which is extracted with CH2Cl2. The organic layer is dried (MgSO4), concentrated, and the residue is chromatographed (CH2Cl2/methanol, 9/1) to give 150 mg of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:19])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:19])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][NH2:12])=[CH:6][CH:7]=1
Reactant: NC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NCCC(O)(c1ccc(Br)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To 1.0 g (3.1 mmole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0° C. and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred for 48 hours at room temperature, and then cautiously hydrolyzed with water. Alkalization with 2 M NaOH and extraction with ether gave after evaporation a semi-crystalline residue. Recrystallization from ether-petroleum ether gave 0.6 g (63%) of the amine, m.p. 95°-115° C. NMR-spectrum (COCl3): 2H(2.4, 1-CH2)m : 2H(3.0, 2-CH2)m : 3H(3.6, --OH, --NH2)b : 6H(7.1-8.0 ArH)m : 2H(8.6)m ##STR30##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31]1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:36][CH2:35][CH:32]5[CH2:33][CH2:34][N:30]([CH3:29])[CH2:31]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CN1CCC(CN)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Solvent: C1COCCO1
Product: CN1CCC(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 120 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), C-(1-Methyl-pyrrolidin-3-yl)-methylamine (164 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol) tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 120 mg of 117 (yield=34%). 1H NMR (CDCl3, 400 MHz): δ8.67-8.52 (m, 1H), 8.11-8.06 (m, 1H), 7.58-7.50 (m, 1H), 7.16-7.02 (m, 3H), 6.96-6.90 (m, 1H), 6.42-6.31 (m, 1H), 4.28-4.21 (m, 2H), 3.50-2.84 (m, 8H), 2.72-2.64 (m, 3H), 2.38-2.22 (m, 1H), 1.94-1.82 (m, 1H). LC-MS (ESI): m/z=495 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3](O)=[O:4].[CH3:6][S:7]([CH3:10])(=[NH:9])=[O:8].[Cl:11][C:12]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:13]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21].N12CCCCC1C=NCCC2>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:13]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([O:22][CH2:2][C:3]([N:9]=[S:7]([CH3:10])([CH3:6])=[O:8])=[O:4])=[O:21]
Reactant: CS(C)(=N)=O
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)CCl
Agent: C1=NCCCN2CCCCC12
Solvent: Cc1ccccc1
Product: CS(C)(=O)=NC(=O)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
from chloroacetic acid, dimethyl sulphoximine and 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoic acid using 1,5-diaza-bicyclo[5,4,0]undec-5-ene as the base and toluene as the solvent there is obtained N-{[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyloxy]acetyl}-S,S-dimethyl-sulphoximine as a yellow resin; 1H-NMR (CDCl3): 8.23-6.92 (m, 6H), 4.87 (s,2H), 3.37 (s,6H);
Reaction SMILES: C([NH:4]CC1SC=C(CN2CCN([C@@H]([C@@H](C)CC)C(OC(C)(C)C)=O)C2=O)N=1)(C)C.C([O-])(O)=O.[Na+].Cl[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]>C(#N)C.O>[C:36]([NH2:4])([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(CNC(C)C)n2)C1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 141.4 %

Procedure:
A solution of the product of Example 283A (59 mg) in acetonitrile (0.9 mL) and water (0.3 mL) was treated with NaHCO3 (34 mg, 2.4 equivalents) followed by 9-fluorenylmethyl chloroformate (53 mg, 1.2 equivalents) at 25° C. for 1.5 h. The solvents were evaporated and the residue was purified using ethyl acetate:chloroform (1:4) to give 47 mg (40%) of FMOC-amine which was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred at 25° C. for 1 h. The solvents were evaporated, and the acid was used directly for the next step.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].C(P(=O)(OCC)[O:9][CH2:10]C)#N.[CH3:16][CH:17]([CH3:29])[CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19]C(O)=O>C(N(CC)CC)C.O1CCCC1>[CH3:1][N:2]([O:9][CH3:10])[C:3](=[O:4])[CH2:19][CH:18]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:17]([CH3:16])[CH3:29]
Reactant: CC(C)C(CC(=O)O)c1ccccc1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)CC(c1ccccc1)C(C)C
Reaction time: 19 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, a dimethylformamide solution of diethyl cyanophosphonate (1.97 g) and triethylamine (1.63 mL) was added to a tetrahydrofuran solution (24 mL) of 4-methyl-3-phenyl-pentanoic acid (1.96 g), N, O—dimethylhydroxyamine hydrochloride (1.18 g) and triethylamine (1.63 mL) at 0° C. After 19 hours, the organic layer was separated by adding diethyl ether and an aqueous saturated ammonium chloride thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give the title compound (1.13 g, 47%).